The overall aims of this revised proposal are to build on existing MRI/functional MRI capacity in South Africa and to apply newly implemented structural and functional imaging techniques to examine brain function in adolescents of the Western Cape region of South Africa who are heavy users of methamphetamine alone or in combination with cannabis. Over the past several years we have initiated a research collaboration between the Brain Imaging Center (BIC) at McLean Hospital, Harvard Medical School and the Brain Imaging Group (BIG) at the University of Stellenbosch made possible through a NIDA sponsored supplementary grant award. The proposed R21 is designed to consolidate and extend this collaboration by training collaborative South African partners in MR methodology and the application of MR techniques while simultaneously collecting data on the effects of methamphetamine and cannabis use. Functional magnetic resonance imaging capacity, recently installed in South Africa, will be expanded by a) providing workshops and tutorials on fundamental concepts underlying MR methods; b) describing strategies for optimization of structural and functional imaging protocols in order to maximize image quality and facilitate optimal co- registration of functional to structural data at the individual level; c) reviewing approaches for development and validation of neurocognitive activation paradigms for use with fMRI; d) training of South African investigators in image processing and analysis of morphometric and functional imaging data to develop independent image analysis capacity using SPM and brain voyager software and; e) evaluating hardware and software needs for implementing MR spectroscopy. These fMRI techniques will be applied to test the hypothesis that frontal dysfunction, as measured by reduced BOLD signal in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) will be present in adolescents, aged 13-17, of the Western Cape region of South Africa, who are heavy users of methamphetamine alone (n=10) or in combination with cannabis (n=10), relative to matched non-using controls (n=10). An R01 application will then be prepared based on the data acquired during the R21 period. [unreadable] [unreadable] [unreadable]